1. Field of the Invention
This invention relates to a method for treating mammals, preferably humans, who suffer from unwanted immune responses. In particular, it relates to methods for ameliorating LFA-1-mediated disorders, such as those caused by transplanted grafts and immune diseases.
2. Description of Background and Related Art
The treatment of disorders and diseases mediated by T lymphocytes has been addressed through many routes. Rheumatoid arthritis (RA) is one such disorder. Current therapy for RA includes bed rest, application of heat, and drugs. Salicylate is the currently preferred drug, particularly as other alternatives such as immunosuppressive agents and adrenocorticosteroids can cause greater morbidity than the underlying disease itself. Nonsteroidal anti-inflammatory drugs are available, and many of them have effective analgesic, anti-pyretic and anti-inflammatory activity in RA patients. These include indomethacin, phenylbutazone, phenylacetic acid derivatives such as ibuprofen and fenoprofen, naphthalene acetic acids (naproxen), pyrrolealkanoic acid (tometin), indoleacetic acids (sulindac), halogenated anthranilic acid (meclofenamate sodium), piroxicam, and diflunisal.
Other drugs for use in RA include anti-malarials such as chloroquine, gold salts and penicillamine. These alternatives frequently produce severe side effects, including retinal lesions and kidney and bone marrow toxicity. Immunosuppressive agents such as methotrexate have been used only in the treatment of severe and unremitting RA because of their toxicity. Corticosteroids also are responsible for undesirable side effects (e.g., cataracts, osteoporosis, and Cushing's disease syndrome) and are not well tolerated in many RA patients.
Another disorder mediated by T lymphocytes is rejection of host or grafts after transplantation. Attempts to prolong the survival of transplanted allografts and xenografts, or to prevent graft versus host rejection, both in experimental models and in medical practice, have centered mainly on the suppression of the immune apparatus of the recipient. This treatment has as its aim preventive immunosuppression and/or treatment of graft rejection.
Examples of agents used for preventive immunosuppression include cytotoxic drugs, anti-metabolites, corticosteroids, and anti-lymphocytic serum. Nonspecific immunosuppressive agents found particularly effective in preventive immunosuppression (azathioprine, bromocryptine, methylprednisolone, prednisone, and most recently, cyclosporin A) have significantly improved the clinical success of transplantation. The nephrotoxicity of cyclosporin A after renal transplantation has been reduced by co-administration of steroids such as prednisolone, or prednisolone in conjunction with azathioprine. In addition, kidneys have been grafted successfully using anti-lymphocyte globulin followed by cyclosporin A. Another protocol being evaluated is total lymphoid irradiation of the recipient prior to transplantation followed by minimal immunosuppression after transplantation.
Treatment of rejection has involved use of steroids, 2-amino-6-aryl-5-substituted pyrimidines, heterologous anti-lymphocyte globulin, and monoclonal antibodies to various leukocyte populations, including OKT-3. See generally J. Pediatrics, 111: 1004-1007 (1987), and specifically U.S. Pat. No. 4,665,077.
The principal complication of immunosuppressive drugs is infections. Additionally, systemic immunosuppression is accompanied by undesirable toxic effects (e.g., nephrotoxicity when cyclosporin A is used after renal transplantation) and reduction in the level of the hemopoietic stem cells. Immunosuppressive drugs may also lead to obesity, poor wound healing, steroid hyperglycemia, steroid psychosis, leukopenia, gastrointestinal bleeding, lymphoma, and hypertension.
In view of these complications, transplantation immunologists have sought methods for suppressing immune responsiveness in an antigen-specific manner (so that only the response to the donor alloantigen would be lost). In addition, physicians specializing in autoimmune disease strive for methods to suppress autoimmune responsiveness so that only the response to the self-antigen is lost. Such specific immunosuppression generally has been achieved by modifying either the antigenicity of the tissue to be grafted or the specific cells capable of mediating rejection. In certain instances, whether immunity or tolerance will be induced depends on the manner in which the antigen is presented to the immune system.
Pretreating the allograft tissues by growth in tissue culture before transplantation has been found in two murine model systems to lead to permanent acceptance across MHC barriers. Lafferty et al., Transplantation, 22: 138-149 (1976); Bowen et al., Lancet, 2:585-586 (1979). It has been hypothesized that such treatment results in the depletion of passenger lymphoid cells and thus the absence of a stimulator cell population necessary for tissue immunogenicity. Lafferty et al., Annu. Rev. Immunol., 1: 143 (1983). See also Lafferty et al., Science, 188: 259-261 (1975) (thyroid held in organ culture), and Gores et al., J. Immunol., 137: 1482-1485 (1986) and Faustman et al., Proc. Natl. Acad. Sci. U.S.A., 78: 5156-5159 (1981) (islet cells treated with murine anti-Ia antisera and complement before transplantation). Also, thyroids taken from donor animals pretreated with lymphocytotoxic drugs and gamma radiation and cultured for ten days in vitro were not rejected by any normal allogeneic recipient. Gose and Bach, J. Exp. Med., 249: 1254-1259 (1979). All of these techniques involve depletion or removal of donor lymphocyte cells.
In some models such as vascular and kidney grafts, there exists a correlation between Class II matching and prolonged allograft survival, a correlation not present in skin grafts. Pescovitz et al., J. Exp. Med., 160: 1495-1508 (1984); Conti et al., Transplant, Proc., 19: 652-654 (1987). Therefore, donor-recipient HLA matching has been utilized. Additionally, blood transfusions prior to transplantation have been found to be effective. Opelz et al., Transplant. Proc., 4: 253 (1973); Persijn et al., Transplant. Proc., 23: 396 (1979). The combination of blood transfusion before transplantation, donor-recipient HLA matching, and immunosuppression therapy (cyclosporin A) after transplantation was found to improve significantly the rate of graft survival, and the effects were found to be additive. Opelz et al., Transplant. Proc., 17: 2179 (1985).
The transplantation response may also be modified by antibodies directed at immune receptors for MHC antigens. Bluestone et al., Immunol. Rev. 90: 5-27 (1986). Further, graft survival can be prolonged in the presence of antigraft antibodies, which lead to a host reaction that in turn produces specific immunosuppression. Lancaster et al., Nature, 315: 336-337 (1985).
The immune response of the host to MHC antigens may be modified specifically by using bone marrow transplantation as a preparative procedure for organ grafting. Thus, anti-T-cell monoclonal antibodies are used to deplete mature T cells from the donor marrow inoculum to allow bone marrow transplantation without incurring graft-versus-host disease. Mueller-Ruchholtz et al., Transplant Proc., 8: 537-541 (1976). In addition, elements of the host's lymphoid cells that remain for bone marrow transplantation solve the problem of immunoincompetence occurring when fully allogeneic transplants are used.
Lymphocyte adherence to endothelium is a key event in the process of inflammation. There are at least three known pathways of lymphocyte adherence to endothelium, depending on the activation state of the T cell and the endothelial cell. T cell immune recognition requires the contribution of the T cell receptor as well as adhesion receptors, which promote attachment of T cells to antigen-presenting cells and transduce regulatory signals for T cell activation. The lymphocyte function associated (LFA) antigen-1 (LFA-1, CD11a, .alpha.-chain/CD18, .beta.-chain) has been identified as the major integrin receptor on lymphocytes involved in these cell adherence interactions leading to several pathological states. ICAM-1, the endothelial cell immunoglobulin-like adhesion molecule, is a known ligand for LFA-1 and is implicated directly in graft rejection, psoriasis, and arthritis.
LFA-1 is required for a range of leukocyte functions, including lymphokine production of helper T cells in response to antigen-presenting cells, killer T cell-mediated target cell lysis, and immunoglobulin production through T cell-B cell interactions. Activation of antigen receptors on T cells and B cells allows LFA-1 to bind its ligand with higher affinity.
Monoclonal antibodies (MAbs) directed against LFA-1 led to the initial identification and investigation of the function of LFA-1. Davignon et al., J. Immunol., 127: 590 (1981). LFA-1 is present only on leukocytes [Krenskey et al., J. Immunol., 131: 611 (1983)], and ICAM-1 is distributed on activated leukocytes, dermal fibroblasts, and endothelium. Dustin et al., J. Immunol., 137: 245 (1986).
Previous studies have investigated the effects of anti-CD11a MAbs on many T-cell-dependent immune functions in vitro and a limited number of immune responses in vivo. In vitro, anti-CD11a MAbs inhibit T-cell activation [Kuypers et al., Res. Immunol., 140: 461 (1989)], T-cell-dependent B-cell proliferation and differentiation [Davignon et al., supra; Fischer et al., J. Immunol., 136: 3198 (1986)], target cell lysis by cytotoxic T lymphocytes [Krensky et al., supra], formation of immune conjugates [Sanders et al., J. Immunol., 137: 2395 (1986); Mentzer et al., J. Immunol., 135: 9 (1985)], and the adhesion of T-cells to vascular endothelium. Lo et al., J. Immunol., 143: 3325 (1989). Also, the antibody 5C6 directed against CD11b/CD18 was found to prevent intra-islet infiltration by both macrophages and T cells and to inhibit development of insulin-dependent diabetes mellitis in mice. Hutchings et al., Nature, 348: 639 (1990).
The observation that LFA-1-ICAM-1 interaction is necessary to optimize T cell function in vitro, and that anti-CD11a MAbs induce tolerance to protein antigens [Benjamin et al., Eur. J. Immunol., 18: 1079 (1988)] and prolongs tumor graft survival in mice [Heagy et al., Transplantation, 37: 520-523 (1984)] was the basis for testing the MAbs to these molecules for prevention of graft rejection in humans.
Experiments have also been carried out in primates. For example, based on experiments in monkeys it has been suggested that a MAb directed against ICAM-1 can prevent or even reverse kidney graft rejection. Cosimi et al., "Immunosuppression of Cynomolgus Recipients of Renal Allografts by R6.5, a Monoclonal Antibody to Intercellular Adhesion Molecule-1," in Springer et al. (eds.), Leukocyte Adhesion Molecules (New York: Springer, 1988), p. 274; Cosimi et al., J. Immunology, 144: 4604-4612 (1990). Furthermore, the in vivo administration of anti-CD11a MAb to cynomolgus monkeys prolonged skin allograft survival. Berlin et al., Transplantation, 53: 840-849 (1992).
The first successful use of a rat anti-murine CD11a antibody (25-3; IgG1) in children with inherited disease to prevent the rejection of bone-marrow-mismatched haploidentical grafts was reported by Fischer et al., Lancet, 2: 1058 (1986). Minimal side effects were observed. See also Fischer et al., Blood, 77: 249 (1991); van Dijken et al., Transplantation, 49: 882 (1990); and Perez et al., Bone Marrow Transplantation, 4: 379 (1989). Furthermore, the antibody 25-3 was effective in controlling steroid-resistant acute graft-versus-host disease in humans. Stoppa et al., Transplant. Int., 4: 3-7 (1991).
However, these results were not reproducible in leukemic adult grafting with this MAb [Maraninchi et al., Bone Marrow Transplant, 4: 147-150 (1989)], or with an anti-CD18 MAb, directed against the invariant chain of LFA-1, in another pilot study. Baume et al., Transplantation, 47: 472 (1989) Furthermore, a rat anti-murine CD11a MAb, 25-3, was unable to control the course of acute rejection in human kidney transplantation. LeMauff et al., Transplantation, 52: 291 (1991).
A review of the use of monoclonal antibodies in human transplantation is provided by Dantal and Soulillou, Current Opinion in Immunology, 3: 740-747 (1991).
A recent report showed that brief treatment with either anti-LFA-1 or anti-ICAM-1 MAbs minimally prolonged the survival of primarily vascularized heterotopic heart allografts in mice. Isobe et al., Science, 255: 1125 (1992). However, combined treatment with both MAbs was required to achieve long-term graft survival in this model.
Independently, it was shown that treatment with anti-LFA-1 MAb alone potently and effectively prolongs the survival of heterotopic (ear-pinnae) nonprimarily vascularized mouse heart grafts using a maximum dose of 4 mg/kg/day and treatment once a week after a daily dose. Nakakura et al., J. Heart Lung Transplant., 11: 223 (1992). [See also The New York Times, p. B6 (Tuesday, Mar. 10, 1992) "New Technique in Lab Prevents Rejection of Organ Transplants," by Sandra Blakeslee.] Nonprimarily vascularized heart allografts are more immunogenic and more resistant to prolongation of survival by MAbs than primarily vascularized heart allografts. Warren et al., Transplant, Proc., 5: 717 (1973) Trager et al., Transplantation, 47: 587 (1989). The latter reference discusses treatment with antibodies against L3T4 using a high initial dose and a lower subsequent dose.
Another study on treating a sclerosis-type disease in rodents using similar antibodies to those used by Nakakura et al., supra, is reported by Yednock et al., Nature, 356: 63-66 (1992).
Additional disclosures on the use of anti-LFA-1 antibodies and ICAM-1, ICAM-2, and LFA-3 and their antibodies to treat LFA-1-mediated disorders include WO 91/18011 published Nov. 28, 1991, WO 91/16928 published Nov. 14, 1991, WO 91/16927 published Nov. 14, 1991, Can. Pat. Appln. 2,008,368 published Jun. 13, 1991, WO 90/15076 published Dec. 13, 1990, WO 90/10652 published Sep. 20, 1990, EP 387,668 published Sep. 19, 1990, WO 90/08187 published Jul. 26, 1990, EP 379,904 published Aug. 1, 1990, EP 346,078 published Dec. 13, 1989, U.S. Pat. No. 5,071,964, U.S. Pat. No. 5,002,869, Australian Pat. Appln. 8815518 published Nov. 10, 1988, EP 289,949 published Nov. 9, 1988, and EP 303,692 published Feb. 22, 1989.
The above methods successfully utilizing anti-LFA-1 or anti-ICAM-1 antibodies represent an improvement over traditional immunosuppressive drug therapy however, they advocate a higher than minimum or fixed dosage of drug that we expect either to unduly suppress the immune system (and create a significant risk of infection) or to be inadequate for long-term tolerance. There is a need in the art to better treat disorders that are mediated by LFA-1 such as autoimmune diseases, graft vs. host or host vs. graft rejection, and T cell inflammatory responses, so as to minimize side effects and sustain specific tolerance to self- or xenoantigens.
Accordingly, it is an object of this invention to provide an improved method for sustaining resistance to LFA-1 -mediated disorders with minimal side effects.
It is another object to prolong graft survival in transplants.
It is a further object to minimize the toxicity and other adverse effects arising from the use of large doses of immunosuppressants in transplant patients.
It is a still further object to provide the host with selective tolerance to the antigen or agent causing the specific immune disorder, so that the host has a reduced susceptibility to infections and other assaults on the immune system that are opportunistic when conventional immunosuppressive agents or dosages are employed.
These and other objects will become apparent to one of ordinary skill in the art.